Cara L. Alfaro

CYP2D6 status of extensive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, or sertraline.

The aim of this study was to evaluate the CYP2D6 inhibitory effects of four selective rerotonin re-uptake inhibitors (SSRIs). Thirty-one healthy subjects were phenotyped as extensive metabolizers using the dextromethorphan/dextrorphan (DM/DX) urinary ratio as a marker for CYP2D6 activity before and after 8 days of administration of fluoxetine 60 mg (loading dose strategy), fluvoxamine 100 mg, paroxetine 20 mg, or sertraline 100 mg in a parallel-group design. Statistical analysis was performed on log-transformed DM/DX ratios because of variability within and between treatment groups. DM/DX ratios before (DM/DX(BL)) and after (DM/DX(SSRI)) were compared within and between the four SSRI groups. DM/DX(BL) ratios were not significantly different between the four SSRI treatment groups. Comparing within groups, significant differences between DM/DX(BL) and DM/DX(SSRI) were found for the fluoxetine (p < 0.001; ratio values, 0.020 vs. 0.364) and paroxetine (p = 0.0005, ratio values 0.029 vs. 1.085) but not for the fluvoxamine or sertraline groups. Comparing between groups, significant differences in DM/DX(SSRI) ratios were found for fluoxetine versus sertraline (p = 0.0019, DM/DX = 0.364 vs. 0.057), fluoxetine versus fluvoxamine (p < 0.0001, DM/DX = 0.364 vs. 0.019), paroxetine versus sertraline (p = 0.0026, DM/DX = 1.085 vs. 0.057), and paroxetine versus fluvoxamine (p < 0.0001, DM/DX = 1.085 vs. 0.019). No significant differences were noted between the two potent CYP2D6 inhibitors, fluoxetine and paroxetine, or the two weakest inhibitors, fluvoxamine and sertraline. Five subjects in the fluoxetine and four subjects in the paroxetine groups changed to poor metabolizer phenotype (DM/DX > or = 0.3) after treatment. Although CYP2D6 inhibitory effects of fluvoxamine and sertraline did not yield significant differences from baseline, some subjects exhibited DM/DX ratio increases of 150 to 200%. One paroxetine-treated subject did not exhibit any CYP2D6 inhibition. SSRI dose and plasma concentration may be correlated with the extent of CYP2D6 inhibition and should be further investigated.

CYP2D6 Inhibition by Selective Serotonin Reuptake Inhibitors: Analysis of Achievable Steady-State Plasma Concentrations and the Effect of Ultrarapid Metabolism at CYP2D6

Study Objective. To assess the correlation between plasma concentrations of four commonly administered selective serotonin reuptake inhibitors (SSRIs) and the magnitude of cytochrome P450 (CYP) 2D6 inhibition.

Correlation of Antipsychotic and Prolactin Concentrations in Children and Adolescents Acutely Treated with Haloperidol, Clozapine, or Olanzapine

Patients with a Diagnostic and Statistical Manual of Mental Disorders (third edition, revised) diagnosis of schizophrenia or psychotic disorder not otherwise specified with onset of psychosis before the age of 13 participated in 6- to 8-week open or double-blind trials of haloperidol (n = 15, mean dose 15.4 +/- 8.1 mg/day [0.27 +/- 0.15 mg/kg/day]), clozapine (n = 30, mean dose 269.9 +/- 173.3 mg/day [4.4 +/- 2.6 mg/kg/day]), or olanzapine (n = 12, mean dose 17.5 +/- 2.8 mg/day [0.30 +/- 0.13 mg/kg/day]). Blood samples were obtained at 6 weeks for evaluation of haloperidol, reduced haloperidol, clozapine, desmethylclozapine, and olanzapine plasma concentrations and serum prolactin concentrations. No gender differences were noted for antipsychotic dose or concentration within each treatment group. Correlations between antipsychotic plasma concentration and serum prolactin concentration were significant only for the olanzapine treatment group (r = 0.80, p = 0.002). Separate correlations for gender were significant only for females receiving olanzapine (r = 0.91, p = 0.03); the patient with the highest serum prolactin experienced galactorrhea. Further studies evaluating the prolactin-elevating properties of antipsychotics are warranted in this population.

Clozapine-Induced Neutropenia in Children: Management with Lithium Carbonate

Clozapine, an atypical antipsychotic, is the most effective medication for treatment-resistant schizophrenia, but its use is limited by the high risk of neutropenia and agranulocytosis. In children, the rate of clozapine-induced neutropenia is even higher than in adults. We report two cases of children 7- and 12-years old diagnosed with very early onset schizophrenia, who developed neutropenia when treated with clozapine. In both cases addition of lithium carbonate elevated the white blood count (WBC) allowing clozapine rechallenge. WBC and total neutrophil count remained stable long-term with coadministration of clozapine (400-425 mg per day) and lithium with the blood level of 0.8-1.1 microg/mL. This report supports the use of adjunct lithium for clozapine-induced neutropenia as a safe and successful strategy in children.

Clozapine-induced akathisia in children with schizophrenia.

Akathisia is a relatively rare side effect with the newer atypical antipsychotic agents, particularly clozapine, and is easily misdiagnosed in children. As children are often unable to describe their symptoms verbally, their akathisia can be misdiagnosed as worsening of their psychosis, prompting an unnecessary increase in their neuroleptic dose. Two cases of childhood-onset schizophrenia associated with clozapine-induced akathisia responsive to beta-blocker treatment are described. Akathisia should be considered in all cases of apparent nonresponse to atypical antipsychotics.

In vivo inhibition of midazolam disposition by ketoconazole and fluoxetine, and comparison to in vitro prediction

Clinical Pharmacology & Therapeutics (1999) 65, 143–143; doi:

Unanticipated Plasma Concentrations in Two Clozapine-Treated Patients

OBJECTIVE: To report two cases of lower than anticipated clozapine plasma concentrations despite near maximum recommended doses of clozapine 800–900 mg/d in two medication-compliant schizophrenic inpatients. CASE SUMMARIES: Clozapine therapy was initiated in two male schizophrenic inpatients for treatment of psychotic symptoms refractory to other typical and atypical antipsychotics. Despite receiving adequate doses of clozapine for at least two months, these patients remained symptomatic. Therapeutic drug monitoring was used to target a clozapine plasma concentration of ≥250 ng/mL, the minimum value reported in the literature to be associated with increased clinical response. Clozapine plasma concentrations remained at 200 ng/mL in one patient despite dosage increases from 600 to 800 mg/d. In the second patient, administration of the maximum recommended dose resulted in concentrations between 200 and 250 ng/mL. Increasing the clozapine dosage to 1000 mg/d did not increase the clozapine plasma concentration. Evaluation of the ratio of clozapine plasma concentration clozapine to dose yielded lower than expected values compared with those reported in the literature. DISCUSSION: These two patients exhibited lower than anticipated clozapine plasma concentrations despite receiving high doses of clozapine. Several studies evaluating clozapine serum concentrations and clinical response have suggested threshold concentrations of ≥350 ng/mL, ≥370 ng/mL, or ≥420 ng/mL. The only study that randomized patients to three concentration ranges found that patients who achieved a clozapine serum concentration in a medium range (mean 251 ng/mL) responded better than patients in a low range (mean 91 ng/mL) and similar to patients in a high range (mean 396 ng/mL). However, attaining plasma concentrations in this range for these patients proved difficult. Reasons for the low concentrations are unclear and may be related to increased metabolic activity at several cytochrome P450 isoenzymes involved in the metabolism of clozapine. CONCLUSIONS: These cases illustrate lower than anticipated clozapine plasma concentrations despite high-dose clozapine therapy. Strategies to increase clozapine plasma concentrations in such patients might include adding a drug to partially inhibit the metabolism of clozapine. If those strategies are unacceptable based on risk assessment, patient compliance, or other reasons, clinicians may consider addition of a low-dose typical or other atypical antipsychotic drug to augment clozapine response. PharmD, Clinical Pharmacy Specialist for the National Institute of Mental Health; Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, MD

Carbamazepine and/or Fluvoxamine Drug Interaction with Risperidone in a Patient on Multiple Psychotropic Medications

TO THE EDITOR: Patients with treatment-resistant psychotic disorders often receive multiple psychotropic medications. For such patients, knowledge of a drug’s potential to induce or inhibit cytochrome P450 isoenzymes does not ensure accurate prediction of drug interactions. We describe a patient who exhibited elevations in risperidone plasma concentrations secondary to concurrent thioridazine use and elevations in 9hydroxyrisperidone plasma concentrations, the active metabolite of risperidone, in association with carbamazepine dose reduction and concomitant fluvoxamine therapy. Case Report. A 23-year-old man with a 13-year history of schizophrenia was admitted for a clozapine rechallenge. Clozapine was discontinued two years before, after the patient developed agranulocytosis during erythromycin coadministration. Medications at admission included benztropine 3 mg/d, carbamazepine 1000 mg/d, divalproex sodium 5000 mg/d, fluvoxamine 200 mg/d, primidone 400 mg/d, and risperidone 10 mg/d. To reduce the risk of neutropenia, carbamazepine therapy was tapered and discontinued before the initiation of clozapine. Carbamazepine, primidone (and its active metabolite phenobarbital), divalproex sodium, risperidone, and clozapine trough plasma concentrations were measured weekly. Due to the lack of repetitive compulsive behaviors and the documented interaction between clozapine and fluvoxamine, the fluvoxamine dosage was tapered and discontinued during hospitalization. For management of agitation and aggressive behavior during the carbamazepine taper, oral thioridazine 100 mg every hour as needed was added to the treatment regimen. Carbamazepine, fluvoxamine, clozapine, and thioridazine daily doses are shown in Figure 1; the risperidone dose was not altered. Corresponding risperidone, 9-hydroxyrisperidone, clozapine, and desmethyl clozapine plasma concentrations are also shown in Figure 1. Risperidone plasma concentrations increased from 6.6 to 31.0 ng/mL and 9-hydroxyrisperidone plasma concentrations increased from 13 to 55 ng/mL during initiation of thioridazine and discontinuation of carbamazepine. Clozapine plasma concentrations do not represent steady-state conditions since the clozapine dosage was titrated daily. Divalproex sodium, primidone, and phenobarbital plasma concentrations did not change appreciably. The patient’s target symptoms responded well to reinitiation of clozapine without the recurrence of agranulocytosis. Despite the elevation of risperidone and 9hydroxyrisperidone plasma concentrations, this medication regimen was tolerated without serious adverse effects. Discussion. The initial increase in risperidone plasma concentrations coincided with the administration of thioridazine and discontinuation of carbamazepine. From hospital days 4 to 23, the patient received thioridazine 100–500 mg/d. Since this antipsychotic drug has potent CYP2D6inhibiting effects,1 concomitant thioridazine therapy most likely increased the plasma concentration of the CYP2D6 substrate, risperidone. The discontinuation of the CYP3A4 inducer, carbamazepine, may have also contributed to an increase in risperidone plasma concentrations since the role of this isoenzyme in risperidone metabolism has recently been determ i n e d .2 However, the temporal relationship of thioridazine discontinuation with the decrease of risperidone plasma concentrations to baseline values implicates thioridazine in this drug interaction. Since the oxidative metabolic pathways for 9-hydroxyrisperidone are unknown, it is difficult to ascribe plasma concentration elevation to a specific drug interaction. An increase in 9-hydroxyrisperidone could be attributed to the discontinuation of the enzyme inducer, carbamazepine, if the affected enzymes are involved in the metabolism of this active metabolite. One case3 reported a twofold increase in 9-hydroxyrisperidone 10 days after the cessation of carbamazepine. This would not, however, explain the later decline in 9-hydroxyrisperidone plasma concentrations. A potential drug interaction between risperidone and fluvoxamine may have resulted in the increase and subsequent decrease in 9-hydroxyrisperidone. Fluvoxamine is a known CYP3A4, CYP1A2, and CYP2C19 inhibitor. Although the fluvoxamine dose was unaltered when 9-hydroxyrisperidone initially increased, fluvoxamine plasma concentrations may have increased with carbamazepine discontinuation. Fluvoxamine is metabolized primarily by CYP2D6 and the inducible isoenzyme, CYP1A2.4 Since fluvoxamine plasma concentrations were not obtained during the carbamazepine taper, it is not known whether plasma concentrations of